The present invention relates to pyrazolopyrimidinone derivatives of the following formula 1, their preparation method and pharmaceutical compositions containing the said derivatives. The compounds have efficacy on the treatment of impotence, one of male sexual dysfunctions with the side effects reduced. 
Wherein,
R1 represents hydrogen, alkyl group of C1-C6, fluoroalkyl group of C1-C3, or cycloalkyl group of C3-C6;
R2represents hydrogen, substituted or unsubstitutedalkyl group of C2-C6, fluoroalkyl group of C1-C3, or cycloalkyl group of C3-C6;
R3 represents substituted or unsubstituted alkyl group of C1-C6, fluoroalkyl group of C1-C6, cycloalkyl group of C3-C6, alkenyl group of C3-C6, or alkynyl group of C3-C6; and
R4 represents substituted or unsubstituted and linear or branched alkyl group of C1-C10, substituted or unsubstituted alkenyl group of C1-C9, substituted or unsubstituted cycloalkyl group of C3-C6, substituted or unsubstituted benzene, or substituted or unsubstituted heterocycle selected from the group consisting of pyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole, pyrazole, thiadiazole, oxazole, piperidine, morpholine, imidazole, pyrrolidine, thienyl, triazole, pyrrole and furyl ring.
In case of R2, R3 and R4 being substituted, the substituent is alkyl group of C1-C10, cycloalkyl group of C3-C6, halogen, fluoroalkyl group of C1-C6, alkyloxy group of C1-C10, substituted or unsubstituted benzene, or substituted or unsubstituted heterocycle selected from the group consisting of pyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole, pyrazole, thiadiazole, oxazole, piperidine, morpholine, imidazole, pyrrolidine, thienyl, triazole, pyrrole and furyl ring.
The compounds of formula 1 may exist in tautomeric equilibrium represented by the following reaction scheme 1. 
The compounds of formula 1 may contain asymmetric centers and thus they can exist as enantiomers. The present invention includes both mixtures and separate individual isomers.
Male erectile dysfunction is one of the most common sexual dysfunctions in men. Although erectile dysfunction can be primarily psychogenic in origin, it often accompanies chronic illnesses, such as diabetes mellitus, heart disease, hypertension, and a variety of neurological diseases. Its prevalence is strongly related to age, with a estimated prevalence of 2% at age 40 years rising to 25-30% by age of 65. Although no data are available on the prevalence of erectile dysfunction in men aged over 75, it is probably over 50%.
Various treatment options for erectile dysfunction are available, such as counseling, hormonal therapy, self-injection or transurethral application of vasodilator agents, vacuum devices, prosthesis implantation, and venous/arterial surgery. However, these therapeutic options have several limitations such as side effects, high-cost and low efficacy. Therefore it has called for research efforts to develop new, high effective and simple to use treatment methods, potentially oral medication.
Recently, sildenafil has been developed as a therapeutic agent for male erectile dysfunction by oral administration. Sildenafil is the first in a new class of drugs known as inhibiting phosphodiesterase-5 enzyme distributed specifically in corpus cavernosal tissues and induces relaxation of the corpus cavernosal smooth muscle cells, so that blood flow to the penis is enhanced, leading to an erection. Sildenafil has shown a response rate of around 80% in men with erectile dysfunction of organic cause.
On the other hand, U.S. Pat. No. 3,939,161 discloses that 1,3-dimethyl-1H-pyrazolopyrimidinone derivatives exhibit anticonvulsant and sedative activiity, and also exhibit anti-inflammatory activity and gastric antisecretory activity; EP 201,188 discloses that 5-substituted pyrazolopyrimidinone derivatives have effects of antagonizing adenosine receptor and of inhibiting phosphodiesterase enzymes and can be used for the treatment of cardiovascular disorders such as heart failure or cardiac insufficiency; EP 463,756, EP 526,004, WO 93/6,104 and WO 93/7,149 disclose that pyrazolopyrimidinone derivatives which inhibit c-GMP phosphodiesterase more selectively than c-AMP phosphodiesterase have efficacy on cardiovascular disorders such as angina pectoris, hypertension, heart failure, atherosclerosis, chronic asthma, etc.; and WO 94/28,902, WO 96/16,644, WO 94/16,657 and WO 98/49,166 disclose that the known inhibitors of c-GMP phosphodiesterase including the pyrazolopyrimidinone derivatives of the above mentioned patents can be used for the treatment of male erectile dysfunction.
We, the inventors of the present invention, have investigated to develop the improved therapeutic agent for impotence and synthesized new pyrazolo pyrimidinone derivatives which have better potency for the treatment of impotence than that of sildenafil, based on the mechanism of inhibiting phosphodiesterase-5 enzyme. The selectivity over phosphodiesterase-6 distributed in retina and phosphodiesterase-3 distributed in heart, of the compounds of the present invention, is much more improved, to reduce the side effects. The solubility and the metabolism in the liver, which are very important factor affecting the rate of the absorption when administered orally, of the compounds of the present invention is much more improved.
It is an object of the present invention to provide pyrazolopyrimidinone derivatives represented by formula 1 and their pharmaceutically acceptable salts.
It is another object of the present invention to provide preparation method of the said pyrazolopyrimidinone derivatives.
It is still another object of the present invention to provide pharmaceutical compositions for the treatment of impotence which contain the said pyrazolopyrimidinone derivatives and/or their pharmaceutically acceptable salts as an active ingredient.
The present invention provides new pyrazolopyrimidinone derivatives of the following formula 1 and their pharmaceutically acceptable salts. 
Wherein,
R1, represents hydrogen, alkyl group of C1-C6, fluoroalkyl group of C1-C3, or cycloalkyl group of C3-C6;
R2represents hydrogen, substituted or unsubstitutedalkyl group of C2-C6, fluoroalkyl group of C1-C3, or cycloalkyl group of C3-C6;
R3 represents substituted or unsubstituted alkyl group of C1-C6, fluoroalkyl group of C1-C6, cycloalkyl group of C3-C6, alkenyl group of C3-C6, or alkynyl group of C3-C6; and
R4 represents substituted or unsubstituted and linear or branched alkyl group of C1-C10, substituted or unsubstituted alkenyl group of C1-C9, substituted or unsubstituted cycloalkyl group of C3-C6, substituted or unsubstituted benzene, or substituted or unsubstituted heterocycle selected from the group consisting of pyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole, pyrazole, thiadiazole, oxazole, piperidine, morpholine, imidazole, pyrrolidine, thienyl, triazole, pyrrole and furyl ring.
In case of R2, R3 and R4 being substituted, the substituent is alkyl group of C1-C10, cycloalkyl group of C3-C6, halogen, fluoroalkyl group of C1-C6, alkyloxy group of C1-C10, substituted or unsubstituted benzene, or substituted or unsubstituted heterocycle selected from the group consisting of pyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole, pyrazole, thiadiazole, oxazole, piperidine, morpholine, imidazole, pyrrolidine, thienyl, triazole, pyrrole and furyl ring.
In the formula 1, preferably R1 is alkyl group of C1-C3; R2 is substituted or unsubstituted alkyl group of C2-C6; R3 is substituted or unsubstituted alkyl group of C2-C6; and R4 is substituted or unsubstituted alkyl group of C1-C6, substituted or unsubstituted cycloalkyl group of C3-C6, substituted or unsubstitutedbenzene, substituted or unsubstituted pyridine, or substituted or unsubstituted pyrrole. In case of R2, R3 and R4 being substituted, the substituent is preferably halogen, substituted or unsubstituted benzene, substituted or unsubstituted heterocycle selected from the group consisting of pyridine, pyrroldine, piperidine, pyrrole , or substituted or unsubstituted cycloalkyl group of C3-C6.
In the formula 1, more preferably R4 is substituted alkyl group of C1-C6, and the substituent is pyrrolidine.
In particular, the preferable compounds of the present invention are:
1) 5-[2-ethoxy-5-(isopropylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 1);
2) 5-[2-ethoxy-5-(benzylamidosulfonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 2);
3) 5-[2-propyloxy-5-(isopropylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 3);
4) 5-[2-ethoxy-5-(isopropylamidosulfonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 5);
5) 5-[2-ethoxy-5-(propylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 7);
6) 5-[2-ethoxy-5-(propylamidosulfonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 8);
7) 5-[2-ethoxy-5-(butylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 9);
8) 5-[2-ethoxy-5-(2-butylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 10);
9) 5-[2-ethoxy-5-(cyclopropylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 13);
10) 5-[2-ethoxy-5-(cyclopropylamidosulfonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 14);
11) 5-[2-ethoxy-5-(cyclohexylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 19);
12) 5-[2-ethoxy-5-(benzylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 22);
13) 5-[2-propyloxy-5-(benzylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 23);
14) 5-[2-ethoxy-5-(benzylamidosulfonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 24);
15) 5-[2-ethoxy-5-(4-fluorophenylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 26);
16) 5-[2-ethoxy-5-(4-t-butylphenylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 28);
17) 5-[2-ethoxy-5-(4-t-butylphenylamidosulfonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 29);
18) 5-[2-ethoxy-5-(4-isopropylphenylamidosulfonyl) phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 31);
19) 5-[2-ethoxy-5-(4-fluorophenylamidosulfonyl) phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 33);
20) 5-[2-ethoxy-5-(4-pyridylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 34);
21) 5-[2-propyloxy-5-(4-pyridylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 35);
22) 5-[2-ethoxy-5-(4-pyridylamidosulfonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 36);
23) 5-[2-ethoxy-5-(4-pyridylamidosulfonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 37);
24) 5-[2-ethoxy-5-(3-pyridylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 38);
25) 5-[2-propyloxy-5-(3-pyridylamidosulfonyl)phenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 39);
26) 5-[2-ethoxy-5-(3-pyridylamidosulfonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 40);
27) 5-[2-ethoxy-5-(3-pyridylamidosulfonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 41);
28) 5-[2-propyloxy-5-(4-pyridylmethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 44);
29) 5-[2-ethoxy-5-(4-pyridylmethylamidosulfonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo (4,3-d)pyrimidin-7-one (compound of example 46);
30) 5-[2-ethoxy-5-(3-pyridylmethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 47);
31) 5-[2-ethoxy-5-(3-pyridylmethylamidosulfonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 48);
32) 5-[2-propyloxy-5-(3-pyridylmethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 49);
33) 5-[2-ethoxy-5-(2-pyridylmethylamidosulfonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 51);
34) 5-[2-propyloxy-5-(2-pyridylmethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 52);
35) 5-[2-propyloxy-5-(1-methyl-3-pyrrolidinylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 53);
36) 5-[2-ethoxy-5-(1-methyl-3-pyrrolidinylamidosulfonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 54);
37) 5-[2-propyloxy-5-(1-methyl-2-pyrrolidinylmethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 56);
38) 5-[2-ethoxy-5-(1-methyl-2-pyrrolidinylmethylamidosulfonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 58);
39) 5-[2-propyloxy-5-(1-methyl-3-pyrrolidinylmethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 60);
40) 5-[2-ethoxy-5-(1-methyl-3-pyrrolidinylmethylamidosulfonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 62);
41) 5-[2-propyloxy-5-(1-ethyl-3-pyrrolidinylmethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 64);
42) 5-[2-ethoxy-5-(1-ethyl-3-pyrrolidinylmethylamidosulfonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 66);
43) 5-[2-propyloxy-5-(1-methyl-2-pyrrolidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 68); and
44) 5-[2-ethoxy-5-(1-methyl-2-pyrrolidinylethylamidosulfonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one (compound of example 70).
The compounds of formula 1 according to the present invention can be used in the forms of pharmaceutically acceptable salts, in particular, acid additive salts which are prepared by using pharmaceutically acceptable free acid. Preferred free acids are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. and organic acids such as citric acid, tartaric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, p-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, etc. Also the compounds of formula 1 can be used in the forms of pharmaceutically acceptable metal salts, particularly alkali metal salts such as sodium or potassium salts.
In addition, the present invention provides preparation methods of pyrazolopyrimidinone derivatives of formula 1, represented by the following reaction scheme 2. 
Wherein R1, R2, R3 and R4 are each defined as the formula 1.
The process for preparation according to the present invention comprises the steps of:
1) reacting the chlorosulfonated compound of formula (2) and primary amine (3) under the condition of suitable temperature and suitable solvent to give sulfonamide (4) (step 1):
2) reacting the carboxylic acid (4) prepared in step 1 and pyrazoleamine (5) to give an amide (6) by the known method preparing amide from carboxylic acid and amine (step 2); and
3) cyclizing the amide (6) prepared in step 2 to give the desired compound of formula 1 by the known cyclization method used for preparation of pyrimidinone (step 3).
In step 1, a little excess of 2 equivalents of amine may be used, or a little excess of 1 equivalent of amine and 1 equivalent of acid scavenger such as tertiary amine are may be used together. The reaction temperature is preferred below 20xc2x0 C.
The known method preparing amide from carboxylic acid and amine in step 2 is the process, for example, in which carboxyl group is transformed into activated acid chloride or acid anhydride by using thionyl chloride, pivaloyl chloride, trichlorobenzoyl chloride, carbonyldiimidazole, diphenylphosphinic chloride, etc. and followed by reacting with amine group, or the process using coupling agents such as DCC (1,3-dicyclo hexylcarbodiimide) or EEDQ (N-ethoxycarbonyl-2-ethoxy-1,3-dihydroquinoline).
The cyclization process in step 3 may be carried out in the presence of a suitable base and a suitable solvent. Preferred bases which are employed in step 3 are metal alkoxides; metal salts of ammonia; amine; hydrides of alkali metal or alkaline earth metal; hydroxides; carbonates; bicarbonates; and bicyclic amidines such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and DBN (1,5-diazabicyclo[4.3.0]non-5-ene). Preferred solvents which are employed in step 3 are alcohols such as methanol, ethanol, isopropanol, t-butanol, etc.; ethers such as tetrahydrofuran, dimethoxyethane, dioxane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, etc.; acetonitrile; dimethylsulfoxide; dimethylformamide; N-methylpyrrolidin-2-one; and pyridine.
In addition, the present invention provides pharmaceutical compositions for the treatment of impotence containing the compounds of formula 1 as an active ingredient.
The present invention provides pharmaceutical formulations which contain, in addition to non-toxic, inert pharmaceutically suitable excipients, one or more compounds according to the present invention, and methods for their preparation.
The compounds of formula 1 according to the present invention can be administered orally or parenterally and be used in general form of pharmaceutical preparation.
The compounds of the present invention can be prepared for oral or parenteral administration by mixing with generally-used fillers, extenders, binders, wetting agents, disintegrating agents, diluents such as surfactants, or excipients.
The present invention also includes pharmaceutical dosage forms in dosage units. This means that the dosage forms are present in the form of individual parts, for example tablets, capsules, pills, suppositories and ampules. The content of the active compound corresponds to a fraction or a multiple of an individual dose. The dosage units can contain, for example, 1, 2, 3 or 4 times or xc2xd, ⅓ or xc2xc of the individual dose. An individual dose preferably contains the amount of active compound which is administered in one application and which usually corresponds to a whole, one half, one third or a quarter of a daily dose.
Non-toxic inert pharmaceutically suitable excipients are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all types.
Preferred pharmaceutical dosage forms which may be mentioned are tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.
Solid preparations for oral administration are tablets, pill, powders and capsules, liquid preparations for oral administrations are suspensions, solutions, emulsions and syrups, and the above mentioned preparations can contain various excipients such as wetting agents, sweeteners, aromatics and preservatives in addition to generally-used simple diluents such as water and liquid paraffin.
Tablets, capsules, pills and granules can contain the active compound or compounds in addition to the conventional excipients, such as (a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example carboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) disintegrating agents, for example agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, for example paraffin, and (f) absorption enhancers, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol and glycerol monostearate, (h) adsorbents, for example kaolin and bentonite, and (i) lubricants, for example talc, calcium stearate, magnesiumstearate, and solid polyethylene glycols, or mixtures of the substances listed under (a) to (i).
The tablets, capsules, pills and granules can be provided with the conventional coatings, and can also be of a composition such that they release the active compound or compounds only or preferentially in a certain part of the intestinal tract, if appropriate in a delayed manner, examples of embedding compositions which can be used being polymeric substances and waxes.
If appropriate, the active compound or compounds can also be present in microencapsulated form with one or more of the above mentioned excipients.
Pharmaceutical dosage forms for parenteral administration are injections, suspensions, emulsions, lyophilized formulations and suppositories.
Suppositories can contain, in addition to the active compound or compounds, the customary water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cacao fat, higher esters (for example C14-alcohol with C16-fatty acid), witepsol, macrogol, tween 61, laurin fat and glycerol gelatin or mixtures of these substances.
Ointments, pastes, creams and gels can contain, in addition to the active compound or compounds, the customary excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragaanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures of these substances.
Powders and sprays can contain, in addition to the active compound or compounds, the conventioanl excipients, for example lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain the conventional propellants, for example chlorofluorohydrocarbons.
Solutions and emulsions can contain, in addition to the active compound or compounds, the conventioanl excipients, such as solvents, solubilizing agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formalcohol, tetrahydrofurfurylalcohol, polyethyleneglycols and fatty acid esters of sorbitan, or mixtures of these substances.
For parenteral administration, the solutions and emulsions are also be in a sterile form which is isotonic with blood.
Suspensions can contain, in addition to the active compound or compounds, the conventioanl excipients, such as liquid diluents, for example water, ethyl alcohol and propyleneglycol, and suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and ethyl oleate, or mixtures of these substances.
The pharmaceutical dosage forms mentioned can also contain coloring agents, preservatives and additives which improve the smell and taste, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
The above mentioned pharmaceutical dosage forms can also contain other pharmaceutically active compounds in addition to the compounds according to the present invention.
The above mentioned pharmaceutical formulations are prepared in the conventioanl method, for example by mixing the active compound or compounds with the excipient or excipients.
The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical dosage forms in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.
In general, it has proved advantageous to administer the active compound or compounds according to the present invention in total amounts of about 0.01 to about 100 mg/kg, preferably 0.1 to 30 mg/kg, 1-3 times every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. However, it may be necessary to properly deviate from the dosages mentioned, and in particular to do so as a function of the nature and body weight of the object to be treated, of the severity of the disease, of the nature of the formulation and of the route of administration of the medicament and the period or interval within which administration takes place.
Thus in some cases it can suffice to manage with less than the abovementioned amount of active compound, while in other cases the abovementioned amount of active compound must be exceeded. The particular optimum dosage and mode of administration required for the active compounds can be determined by any expert on the basis of his expert knowledge.
The pyrazolopyrimidinone derivatives of formula 1 according to the present invention have more prominent efficacy on the treatment of impotence than sildenafil, an already established therapeutic agent for impotence, based on the mechanism of inhibiting phosphodiesterase-5 enzyme. The selectivities for phosphodiesterase-6 and phosphodiesterase-3, of the compounds according to the present invention, are much better than those of sildenafil, reducing the side effects such as visual disorders or cardiovascular disorders. Furthermore, the solubility in water at pH=2 and 5 is much more improved and the metabolism in rat liver is noticeably decreased in some of the pyrazolopyrimidinone derivatives of the present invention. Therefore the probability of better absorption and better in vivo effect can be expected when administered orally compared with sildenafil and the dose of the compound may be reduced.
Practically and presently preferred embodiments of the present invention are illustrative as shown in the following examples.
However, it will be appreciated that those skilled in the art, on consideration of this disclosure, may make modification and improvements within the spirit and scope of the present invention.
The molecular structure of the compounds of formula 1 according to the present invention was identified by IR spectroscopy, UV spectroscopy, NMR spectroscopy, mass spectroscopy and elemental analysis.